The NMDA receptor (NMDAR) has been implicated in many neuronal processes that underlie normal functions like learning and memory to pathologic conditions such as stroke and ischemia. It is therefore of interest, as well as clinical importance, to understand how this receptor is regulated and modulated. In many brain areas, electrical stimulation causes a rapid extracellular alkaline transient, reaching levels as high as 0.1 - 0.2 unit pH in the hippocampus. This pH shift requires Ca2+ entry, and has been proposed to result from Ca2+-H+ exchange by the plasma membrane Ca2+ATPase. Since currents across NMDARs can be significantly increased by a rise in extracellular pH, it has been proposed that these pH changes can augment NMDAR function. In hippocampal slices, inhibition of extracellular carbonic anhydrase (CA), which catalyzes extracellular buffering, causes a large increase in the magnitude of the alkaline shift, and a concurrent prolongation of synaptic NMDAR currents. Thus extracellular CA can influence NMDAR function through its affect on the evoked pH changes. It is unknown, however, whether these alkaline shifts, are sufficient to augment NMDAR-mediated currents in the absence of CA inhibition. This is the first question to be addressed in this proposal. Extracellular CA activity has been attributed to two isoforms, CA IV and CA XIV. Although CA XIV is found exclusively on neurons in hippocampus, previous studies on mice with one or both of these enzymes knocked out demonstrated that either isoform can catalyze buffering near the cell bodies of hippocampal pyramidal cells. It remains unknown whether one or both of these enzymes catalyzes buffering of the local, synaptically-evoked alkaline shift that can augment synaptic NMDAR currents in the dendrites. This is the second issue to be addressed in this proposal. In summary, experiments will test the hypothesis that (1) synaptically-evoked alkaline shifts have a facilitative influence on post synaptic NMDAR currents, and (2) that CA XIV, being a neuronal enzyme, is principally responsible for extracellular buffering that normally limits post synaptic NMDAR responses in the hippocampus.